JP6498600B2 - 部位特異的な非天然アミノ酸残基を含む抗体、その調製方法、及びその使用方法 - Google Patents
部位特異的な非天然アミノ酸残基を含む抗体、その調製方法、及びその使用方法 Download PDFInfo
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- JP6498600B2 JP6498600B2 JP2015516266A JP2015516266A JP6498600B2 JP 6498600 B2 JP6498600 B2 JP 6498600B2 JP 2015516266 A JP2015516266 A JP 2015516266A JP 2015516266 A JP2015516266 A JP 2015516266A JP 6498600 B2 JP6498600 B2 JP 6498600B2
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Description
本明細書に提供されるのは、部位特異的位置に非天然アミノ酸残基を含む抗体、該抗体を含む組成物、その調製方法、及びその使用方法である。
抗体は、その標的抗原に対する顕著な親和性を有する生体分子である。生来、抗体は、異種タンパク質、細胞、及び生物体の排除又は破壊のための特定の脊椎動物における防御システムの一部として与えられている。特定の脊椎動物に、例えば、感染細胞又は感染性細菌上の異種タンパク質が提示された場合、抗体は、その標的異種タンパク質に結合して、異種実体をその排除又は破壊へと導くことができる。
本明細書に提供されるのは、1以上の部位特異的位置において1以上の非天然アミノ酸残基で修飾された抗体である。これらの部位特異的位置は、非天然アミノ酸残基による天然アミノ酸残基の置換に最適である。ある実施態様において、これらの部位特異的位置における置換は、置換が均一である、すなわち、選択された位置で実質的に修飾されている抗体を生じさせる。ある実施態様において、これらの部位特異的位置の1つ又は複数で置換された抗体は、有利な生産収率、有利な溶解度、有利な結合、及び/又は有利な活性を有する。これらの抗体の特性は、以下の節で詳細に記載されている。
本明細書に提供されるのは、1以上の部位特異的位置に非天然アミノ酸を有する抗体、該抗体を含む組成物、該抗体の作製方法、及びその使用方法である。
本明細書に提供される抗体に言及する場合、以下の用語は、別途示されない限り、以下の意味を有する。別途定義されない限り、本明細書で使用される全ての技術用語及び科学用語は、当業者によって一般に理解されるものと同じ意味を有する。本明細書中の用語に対して複数の定義が存在する場合、別途明記されない限り、この節の定義が優先する。
1)アラニン(A)、グリシン(G);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リジン(K)、ヒスチジン(H);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);
7)セリン(S)、トレオニン(T);及び
8)システイン(C)、メチオニン(M)
(例えば、Creightonの文献、タンパク質:構造及び分子特性(Proteins: Structures and Molecular Properties)(W H Freeman & Co.;第2版(1993年12月)を参照されたい)。
本明細書に提供されるのは、少なくとも1つのポリペプチド鎖のアミノ酸配列中の部位特異的位置に1以上の非天然アミノ酸残基を含む抗体である。
Xaa1-…-(Naap(i))n-…-Xaaq(I)
によって記載することができるポリペプチド鎖を含む。式(I)において、各々のXaaは、任意の同一性のポリペプチド鎖中のアミノ酸を表す。言い換えると、各々のXaaは、任意のアミノ酸、典型的には、任意の天然アミノ酸、又はその変異体であることができる。各々のXaaの右側の上付き文字は、ポリペプチド鎖の一次配列中のアミノ酸の位置を表す。Xaa1は、ポリペプチド鎖中の最初の、すなわち、N末端のアミノ酸を表し、Xaaqは、ポリペプチド鎖中の最後の、すなわち、C末端の、アミノ酸を表す。変数qは、ポリペプチド鎖中のアミノ酸の総数と等しい整数である。各々のNaaは、ポリペプチド鎖中の非天然アミノ酸を表す。有用な非天然アミノ酸は、下の節に記載されている。整数nは、ポリペプチド鎖中の非天然アミノ酸の数を表す。典型的な実施態様において、nは、1よりも大きい整数である。各々の整数p(i)は1よりも大きく、qよりも小さく、変数iは、1〜nまで変化する整数である。各々の整数p(i)は、対応するNaaに対するアミノ酸配列中の部位特異的位置を表す。各々の部位特異的位置p(i)は、本明細書に記載の技術よる、天然アミノ酸と非天然アミノ酸、例えば、Naap(i)との置換に最適である。
非天然アミノ酸は、当業者に公知の任意の非天然アミノ酸であることができる。いくつかの実施態様において、非天然コードアミノ酸は、官能基を含む。官能基は、当業者に公知の任意の官能基であることができる。ある実施態様において、官能基は、標識、極性基、非極性基、又は反応基である。
ある実施態様において、抗体は、上記のような反応基を有する非天然アミノ酸を含む。当業者は、反応基を用いて、抗体を、直接的に又はリンカーを介して間接的に非天然アミノ酸との共有結合を形成することができる任意の分子実体に連結することができる。
親抗体は、限定するものではないが、当業者に公知の又は後に発見される任意の抗体であることができる。親抗体は、限定されないが、ヒト、マウス、ラット、ウサギ、ラクダ、ラマ、ヒトコブラクダ、サル、特に哺乳動物、特にヒト並びに特にマウス及びラットを含む、任意の生物体由来の抗体遺伝子(単数)又は抗体遺伝子(複数)によって実質的にコードされていてもよい。一実施態様において、親抗体は、例えば、患者もしくは対象から、トランスジェニックマウスもしくは他の動物を用いることによって(Bruggemann及びTaussigの文献、1997, Curr. Opin. Biotechnol. 8:455-458)、又は選択方法と併用されるヒト抗体ライブラリーを用いることによって(Griffiths及びDuncanの文献、1998, Curr. Opin. Biotechnol. 9:102-108)得られる、完全にヒトのものであり得る。親抗体は、人工又は天然を含む、任意の源に由来するものであってもよい。例えば、親抗体は、限定されないが、キメラ抗体及びヒト化抗体を含む、改変抗体であるか(Clarkの文献、2000, Immunol. Today 21:397-402)、又はコンビナトリアルライブラリーに由来するものであることができる。さらに、親抗体は、1以上の天然抗体遺伝子によって実質的にコードされる抗体の改変変異体であってもよい。例えば、一実施態様において、親抗体は、親和性成熟によって同定された抗体である。
ペルツズマブ(rhuMAb 2C4)(HER2(DI)、Genentech);アポリズマブ(HLA-DRβ鎖、PDL Pharma); AMG-479(IGF-1R、Amgen); 抗IGF-1R R1507(IGF1-R、Roche); CP 751871(IGF1-R、Pfizer); IMC-A12(IGF1-R、Imclone); BIIB022(IGF-1R、Biogen); Mik-β-1(IL-2Rb(CD122)、Hoffman LaRoche); CNTO 328(IL6、Centocor);抗KIR(1-7F9)(キラー細胞Ig様受容体(KIR)、Novo); Hu3S193(ルイス(y)、Wyeth, Ludwig Institute of Cancer Research); hCBE-11(LTβR、Biogen); HuHMFG1(MUC1、Antisoma/NCl); RAV12(N結合型炭水化物エピトープ、Raven); CAL(副甲状腺ホルモン関連タンパク質(PTH-rP)、University of California); CT-011(PD1、CureTech); MDX-1106(ono-4538)(PD1、Medarex/Ono); MAb CT-011(PD1、Curetech); IMC-3G3(PDGFRa、Imclone);バビツキシマブ(ホスファチジルセリン、Peregrine); huJ591(PSMA、Cornell Research Foundation); muJ591(PSMA、Cornell Research Foundation); GC1008(TGFb(汎)阻害剤(IgG4)、Genzyme);インフリキシマブ(Remicade)(TNFa、Centocor); A27.15(トランスフェリン受容体、Salk Institute、INSERN WO 2005/111082号); E2.3(トランスフェリン受容体、Salk Institute);ベバシズマブ(Avastin)(VEGF、Genentech); HuMV833(VEGF、Tsukuba Research Lab、PCT公開WO/2000/034337号、University of Texas); IMC-18F1(VEGFR1、Imclone); IMC-1121(VEGFR2、Imclone)が挙げられる。
本明細書に記載の抗体は、当技術分野で利用可能な方法及び本明細書に開示される方法を用いて組成物に製剤化することができる。本明細書に開示される化合物はいずれも、適当な医薬組成物中に提供し、好適な投与経路で投与することができる。
好適な医薬賦形剤としては、デンプン、グルコース、ラクトース、スクロース、ゼラチン、麦芽、米、小麦粉、チョーク、シリカゲル、ステアリン酸ナトリウム、モノステアリン酸グリセロール、タルク、塩化ナトリウム、乾燥脱脂乳、グリセロール、プロピレン、グリコール、水、エタノールなどが挙げられる。組成物は、望ましい場合、微量の湿潤剤もしくは乳化剤、又はpH緩衝剤を含有することもできる。これらの組成物は、液剤、懸濁剤、乳剤、錠剤、丸薬、カプセル剤、散剤、持続放出製剤などの形態を取ることができる。経口製剤は、標準的な担体、例えば、医薬等級のマンニトール、ラクトース、デンプン、ステアリン酸マグネシウム、サッカリンナトリウム、セルロース、炭酸マグネシウムなどを含むことができる。好適な医薬担体の例は、E.W. Martinの文献、1990、レミントンの医薬科学(Remington's Pharmaceutical Sciences)、Mack Publishing Coに記載されている。
本明細書に提供される特定の抗体は、当業者に好適とみなされる任意の疾患又は疾病の治療又は予防に使用することができる。通常、治療又は予防方法は、該疾患又は疾病を治療又は予防するための、それを必要とする対象への治療的又は予防的有効量の抗体又は抗体組成物の投与を包含する。
本明細書に提供される抗体は、任意の標的の検出のために、又は当業者に好適と見なされる任意の疾患もしくは疾病の診断のために使用することができる。本方法は、適切な場所、例えば、適切な体、組織、又は細胞内の標的抗原に対する抗体の結合を検出することを包含する。本方法において、抗体と抗原の複合体の形成は、当業者に公知の任意の方法によって検出することができる。例としては、検出用の第二の試薬を使用するアッセイ、ELISA並びに免疫沈降及び凝集アッセイが挙げられる。これらのアッセイの詳細な説明は、例えば、Harlow及びLaneの文献、抗体:実験室マニュアル(Antibodies: A Laboratory Manual)(Cold Spring Harbor Laboratory, New York 1988 555-612)、Maertens及びStuyverのWO96/13590号、Zreinらの文献(1998)、及びWO96/29605号に示されている。
本明細書に記載の抗体は、限定するものではないが、当業者に明らかな任意の技術によって調製することができる。調製のための有用な技術としては、例えば、修飾されたtRNAとtRNAシンセターゼを用いるインビボ合成、例えば、修飾されたtRNAとtRNAシンセターゼを用いる無細胞合成、固相ポリペプチド合成、及び液相ポリペプチド合成が挙げられる。例示的な技術は、本節及び下記の実施例に記載されている。
抗体を、その予想される活性について、又は新しい活性について、当業者に明らかな任意のアッセイに従ってアッセイすることができる。得られた抗体を、機能アッセイで活性について、又は非機能アッセイ、例えば、免疫染色、ELISA、クマシー染色もしくは銀染色されたゲル上での定量などで存在するタンパク質の量を定量し、全タンパク質に対する生体活性タンパク質の割合を決定することによって、アッセイすることができる。
本明細書で使用されるように、これらのプロセス、スキーム、及び実施例で使用される記号及び慣例は、特定の略語が具体的に定義されているかどうかにかかわらず、現在の科学文献、例えば、Journal of Biological Chemistryで使用されているものと一致する。
(非天然アミノ酸を含有する例示的な抗体の合成及び例示的な細胞毒性剤へのコンジュゲーション)
以下の実施例は、規定の位置に非天然アミノ酸を含有する例示的な抗体を、その構築方法及び発現方法とともに記載している。該抗体を、発現、抑制効率、細胞殺傷剤とのコンジュゲーション効率、細胞結合、及び細胞殺傷について、下記のように評価した。この実施例では、例示的な抗体は、親抗体トラスツズマブをベースにしている(米国特許第6,165,464号及び2006/0018899 A1号; Carterらの文献、1992, Proc. Natl. Acad. Sci. USA 10:4285-4289)。
(例示的な抗体-薬物コンジュゲートの特徴付け)
試料を定量するために、及びトラスツズマブ変異体薬物コンジュゲートの薬物-抗体比を決定するために、次のように、疎水性相互作用クロマトグラフィー(HIC)を実施した。試料及び標準を、ミリQ水中に調製した3M硫酸アンモニウム(EMD Chemical)、50mMリン酸ナトリウムpH 7.0(Mallinckrodt)に1:2希釈した。Agilent 1100バイナリーポンプHPLCシステムに、Tosoh Bioscience LLC TSK-ゲルButyl-NPR(登録商標)(4.6mm×3.5cm)カラムを、30℃のカラム区画温度にして装備した。移動相Aは、1.5M硫酸アンモニウム、50mMリン酸ナトリウム、pH 7.0であった。移動相Bは、80:20の水:イソプロピルアルコール(Honeywell)中の50mMリン酸ナトリウム、pH 7.0であった。移動相は、1.0mL/分の流速で供給した。分離は、10分間に15%移動相Bから100%移動相Bの線形勾配で実施した。UVデータは、210nmと280nmの両方で取得した。ピーク面積は、Chemstationソフトウェア(Agilent)を用いて定量し、薬物抗体比(DAR)は、全ピーク面積のパーセントから算出した。
(例示的な抗体-薬物コンジュゲートにおける非天然アミノ酸の組み込みの忠実度)
この実施例は、例示的な抗体-薬物コンジュゲートへの非天然アミノ酸の組み込みの忠実度の評価を記載している。S136で置換されるp-アジド-フェニルアラニンで置換され、DBCO-MMAFとコンジュゲートされたトラスツズマブをトリプシンで消化し、ナノ-エレクトロスプレーChipCube源を備えたAgilent 6520 Accurate Mass Q-TOF LC-MSシステムで分析した。誤って組み込まれた可能性のあるアミノ酸及びその野生型対応物を含有するペプチドを、LC-MSデータからの抽出イオンクロマトグラムを用いて、z=1〜4の電荷状態のペプチドについての理論m/zの±10ppm以内で検索した。実測ピークのm/zが、理論m/zの±10ppm以内、かつ正確な電荷状態である場合、それを、MS/MS検証までの潜在的一致とみなした。誤組み込みによるシグナルがない場合は、シグナルを質量スペクトル中のノイズ以下のものであると考えた。最小忠実度率をノイズ対シグナル比として算出した。シグナルを、最も豊富な電荷状態についてのペプチドの溶出プロファイルにわたる全モノアイソトピックイオンの平均として測定し、ノイズを、最小量のシグナルを示す領域に隣接する領域中の同じスペクトル中で推定した。誤組み込み事象を含む観測ペプチドが見つかった場合、その平均シグナルをノイズ測定の代わりに使用した。
(例示的な抗体-薬物コンジュゲートの熱安定性の評価)
この実施例は、非グリコシル化トラスツズマブ及びトラスツズマブ変異体の熱安定性(Tm)を測定するために設計された実験を記載している。熱シフトアッセイを、アッセイすべきタンパク質(Sutroceptin及び変異体)を環境感受性色素(SYPRO Orange, Life Technologies Cat #S-6650)と緩衝化溶液(PBS)中で混合し、該混合物の蛍光を、それが制御された熱変性を受けているときにリアルタイムでモニタリングすることによって実施した。アッセイ混合物中のタンパク質の最終濃度は100〜250μg/mLであり、色素はオリジナルストックから1:1000希釈した(ストック色素はDMSO中5000×である)。タンパク質-色素混合物の5μLアリコートを384-ウェルマイクロプレート(Bio-Rad Cat #MSP-3852)に分配した後、プレートを光学的に透明なシーリングフィルム(Bio-Rad Cat #MSB-1001)で密閉し、384-ウェルプレートリアルタイムサーマルサイクラー(Bio-Rad CFX384 Real Time System)に入れた。タンパク質-色素混合物を、各温度で3秒間平衡化させて、1サイクル当たり0.1℃ずつ(1分当たり〜1.5℃)、25℃から95℃に加熱し、その後、蛍光測定を行った。実験の最後に、Bio-Rad CFXマネージャーソフトウェアを用いて、融解温度(Tm)を決定した。複雑な熱転移プロファイルを有するタンパク質試料については、融解温度(Tm)を、温度(X-軸)に対する蛍光強度(Y-軸)の負の一階微分プロットから、又はデータをボルツマンシグモイドモデルにフィッティングさせることによって算出する。野生型タンパク質と比較したIgG変異体の融解温度の差が、アッセイされているタンパク質についての熱シフトの大きさである。
(RF-1減弱化抽出物におけるHC-F404の発現の評価)
非天然アミノ酸の組み込みに対するRF-1減弱化大腸菌株の使用の効果をまず評価するために、RF-1陽性株であまり発現されない12の変異体を発現させ、RF-1減弱化株でスケールアップした。そのような変異体の1つであるHC-F404は、以下で論じるような、並外れて望ましい特性を示した。
(例示的な抗体-薬物コンジュゲートの特徴付け:終結因子解析)
(TAGスキャンI 方法及び選択された変異体のリスト)
無細胞タンパク質合成反応に使用される無細胞抽出物をOmpT感受性RF-1減弱化大腸菌株から調製した。この株は、アンバー停止コドンで非天然アミノ酸を挿入するための直交CUAをコードするtRNAを産生するようにも改変されている。DNA鋳型の添加後、無細胞反応液を、フラワープレート(m2p-labs # MTP-48-B)中、650rpmで、シェーカー上で、30℃で12時間インキュベートした。軽鎖変異体(軽鎖上にnnAA組み込みを有する変異体)の合成のために、4ug/mLの軽鎖DNA対8μg/mLの重鎖DNAのDNA比を用いた。各々のトラスツズマブ変異体を、1mLスケールで、48-ウェルフラワープレート中、単独で(in singlicate)産生した。合計6枚のプレートを用いて、該変異体を発現させた。
(例示的な抗体-薬物コンジュゲートの特徴付け:さらなる終結因子解析)
(TAGスキャンII 方法及び選択された変異体のリスト)
無細胞タンパク質合成反応に使用される無細胞抽出物をOmpT感受性RF-1減弱化大腸菌株から調製した。この株は、アンバー停止コドンで非天然アミノ酸(p-アジド-フェニルアラニン)を挿入するための直交CUAをコードするtRNAを産生するようにも改変されている。DNA鋳型の添加後、無細胞反応液を、フラワープレート(m2p-labs # MTP-48-B)中、650rpmで、シェーカー上で、30℃で12時間インキュベートした。軽鎖変異体(軽鎖上にnnAA組み込みを有する変異体)の合成のために、4μg/mLの軽鎖DNA対8μg/mLの重鎖DNAのDNA比を用いた。各々のトラスツズマブ変異体を、1mLスケールで、48-ウェルフラワープレート中、単独で産生した。合計6枚のプレートを用いて、該変異体を発現させた。
(例示的な抗体-薬物コンジュゲートの特徴付け:スケールアップ解析)
(TAG IIスキャンからの選択された変異体のスケールアップ)
さらなる特徴付けのための材料を作製するために、DAR及び細胞殺傷データに基づいて、望ましい特徴を有するトラスツズマブ変異体のサブセットを小規模無細胞発現用に選んだ。小規模産生用に選択された重鎖変異体は: R019、S025、I051、S070、D098、T110、S112、K121、S136、Y180、S187、S190、K214、E216、D221、及びK222であった。小規模産生用に選択された軽鎖変異体は:(-)1、S007、P008、G016、T022、S063、R014、D070、N138、R142、E143、及びN152であった。
(例示的な抗体-薬物コンジュゲートの特徴付け: Thermofluor解析)
変異体のThermofluor解析を先に記載されている通りに実施した。Thermofluorの結果を表10に示す。
(例示的な抗体-薬物コンジュゲートの特徴付け:動力学解析)
(選択された変異体のコンジュゲーション動力学)
コンジュゲーションの割合を、幅広い薬物対抗体コンジュゲート比を示す5つの変異体について決定した。該変異体を、薬物(DBCO-MMAF)と、PBS(pH7.4)中、20℃で、2連で、15分間、30分間、1時間、2時間、4時間、8時間、及び16時間混合することにより、反応を開始させた。混合物中の抗体の最終濃度は、0.2〜2uMの範囲である。全ての反応についての最終薬物濃度は100uMである。インキュベーション期間の最後に、アジ化Naを混合物に10mMの最終濃度まで添加した。最終混合物を、先に記載されている通りにZeba及びMustangQプレートにより精製した。IgGの濃度を、Herceptinを質量標準として用いて、Caliperにより決定した。完全コンジュゲート型変異体の割合を、先に記載されている通りに、HICにより決定した。
(例示的な抗体-薬物コンジュゲートの特徴付け:抑制比較解析)
(パラ-アジドフェニルアラニン(pAzF)及びパラ-アジドメチルフェニルアラニン(pAzMeF)による抑制の比較)
広範な抑制効率を有する11の変異体を、下記の変更を加えて、Zawadaらの文献、2011, Biotechnol. Bioeng.108(7): 1570-1578に記載されている通りに、次のように、無細胞タンパク質合成反応で発現させた。非置換トラスツズマブも対照として作製した。tRNA及びOmpT感受性RF1(株16/23の80/20ブレンド)を含む無細胞抽出物を、RT(20℃)で30分間、50μMのヨードアセトアミドで処理し、GSSG、非天然アミノ酸、tRNAシンセターゼ、T7 RNAP、DsbC、PDI、及び鋳型DNAを除く全ての他の成分を含むプレミックスに添加した。その後、DNAを除く全ての残りの試薬を該混合物に添加した。無細胞反応を、選択された変異体のプラスミドDNAの添加により開始させ、96ディープウェルプレート中、450rpmで、シェーカー上で、30℃で12時間インキュベートした。反応液を4℃で5時間さらにインキュベートした。タンパク質合成反応液中の最終濃度は、30%細胞抽出物、0.37mg/mLのメタノカルドコックス・ヤンナスキイpAzF特異的アミノ-アシルtRNAシンセターゼ(FRS)を伴う1mMのパラ-アジドフェニルアラニン(pAzF)(RSP Amino Acids)又は0.37mg/mLのp-シアノフェニルアラニン特異的アミノアシル-tRNAシンセターゼ(Youngらの文献、2011, Biochem. 50: 1894-1900)を伴う1mMのパラ-アジドメチルフェニルアラニン(pAzMeF)、2mMのGSSG、0.29mg/mLのPDI(Mclab)、100μg/mLの大腸菌DsbC、8mMのグルタミン酸マグネシウム、10mMのグルタミン酸アンモニウム、130mMのグルタミン酸カリウム、35mMのピルビン酸ナトリウム、1.2mMのAMP、各々0.86mMのGMP、UMP、及びCMP、2mMのアミノ酸(チロシン及びフェニルアラニンの場合の0.5mMを除く)、4mMのシュウ酸ナトリウム、1mMのプトレシン、1.5mMのスペルミジン、15mMのリン酸カリウム、100nMのT7 RNAP、2μg/mLのトラスツズマブ軽鎖DNA、8μg/mLのトラスツズマブ-(His)6重鎖DNAであった。各々のトラスツズマブ変異体を、各々の変異体について14Cを用いて、100uLスケールで、96ディープウェルプレート中、2連で産生した。このようにして産生されたトラスツズマブ変異体は全て、グリコシル化されていなかったことに留意すべきである。
(別の抗体への非天然アミノ酸組み込み部位の移転)
非天然アミノ酸の組み込み部位を、予測可能なDARを有する2つの異なるIgG配列間で移転することができるかどうかを検討するために、代表的な部位で非天然アミノ酸を含む第二の抗体を評価した。この実験のために、ブレンツキシマブを第二の抗体(配列番号:3及び配列番号:4参照)として選んだ。いくつかの部位を、様々なDARを示すトラスツズマブ突然変異生成研究から選んだ。重鎖において、部位は、K121、Y180、K133、S157、F126、及びP127(EU付番)に対応した。軽鎖において、部位は、R142、N152、Q147、E161、K149、及びQ155(EU付番)に対応した。標準的な迅速変化に基づく部位特異的突然変異生成を用いて、TAG停止コドンをブレンツキシマブ配列中に挿入し、各々の変異体の同一性をDNAシークエンシングにより確認した。無細胞タンパク質合成反応を推進させる鋳型として使用するためのミニプレップDNAを、Qiagenキットを用いて調製した。
非グリコシル化変異体のDARをLC-MSにより次のように決定した。
(LCMSによるADC)
試料を、Xevo QTOFに接続されたWaters Aquity UPLCシステムかけた。タンパク質を、Agilent PLRP-Sカラム(2.3×50mm、5μm、4000Å)で、80℃で分離した。移動相:A: 0.1%ギ酸水; b: 20:80のイソプロパノール:アセトニトリル、0.1%ギ酸。試料を、カラムで、10%Bで0.4分間、その後、30%Bから40%Bまで7分間かけて、40%Bから60%Bへ3分間かけて、ステップ勾配で脱塩した。データを、35Vのコーン電圧を用いて、全LC溶出にわたって取得した。スペクトルを、MassLynxソフトウェアを用いて分析した。DAR値を加重平均として算出した。これを表13に示す。
ADCの代替スキャフォールドとしてのscFvの使用の実現可能性を示すために、アンバーコドンを有するトラスツズマブscFv(VL_VH)をコードするDNAを発現ベクターpYD317にクローニングした。位置(-1)のアミノ酸セリンに対応するヌクレオチドでの重複PCR突然変異生成によって、TAGコドン挿入した。
ADCの代替スキャフォールドとしてのscFv Fcの使用の実現可能性を示すために、アンバーを有するトラスツズマブscFv Fc(VL_VH_Fc)をコードするDNAを発現ベクターpYD317にクローニングした。位置(-1)、Fc R355、Fc N389、及びFc F404(EUインデックス付番)のアミノ酸セリンに対応するヌクレオチドでの重複PCR突然変異生成によって、TAGコドン挿入した。
この実施例は、CD74に特異的な抗体を用いて調製され、かつ本明細書に記載の様々な例示的なリンカー-ウォーヘッド組合せを含む例示的な抗体-薬物コンジュゲートを提供するものである。この実施例はさらに、該リンカー-ウォーヘッド組合せのうちのいくつかとコンジュゲートされたトラスツズマブから調製された例示的な抗体-薬物コンジュゲートを提供するものである。
(配列表)
<210> 配列番号1
<211> 長さ: 449
<212> タイプ: PRT
<213> 生物体:人工配列
<220> 特徴:
<223> 他の情報:配列は合成されたものである。
<400> 配列: 1
<211> 長さ: 214
<212> タイプ: PRT
<213> 生物体:人工配列
<220> 特徴:
<223> 他の情報:配列は合成されたものである。
<400> 配列: 2
> ブレンツキシマブ重鎖:HC-6Hisの配列
> ブレンツキシマブ軽鎖:LCの配列
> 抗CD74重鎖:HCの配列
> 抗CD74軽鎖の配列
本件出願は、以下の構成の発明を提供する。
(構成1)
KabatもしくはChothia付番スキームによる重鎖もしくは軽鎖残基H404、H121、H180、H241、L22、L7、L152、H136、H25、H40、H119、H190、H222、H19、H52、もしくはH70からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む抗体、又はその翻訳後修飾変異体。
(構成2)
KabatもしくはChothia付番スキームによる重鎖もしくは軽鎖残基H404、H121、H180、H241、L22、L7、L152、H136、H25、H40、H119、 H190、及びH222からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、構成1記載の抗体、又はその翻訳後修飾変異体。
(構成3)
KabatもしくはChothia付番スキームによる重鎖もしくは軽鎖残基H404、H121、H180、H241、L22、L7、L152、及びH136からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、構成1記載の抗体、又はその翻訳後修飾変異体。
(構成4)
配列番号1との少なくとも70%、80%、もしくは90%の相同性を有し、かつ配列番号1による代表的な重鎖ポリペプチドの残基404、121、180、241、136、25、40、119、190、222、19、52、もしくは70に対応する部位からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、構成1記載の抗体、又はその翻訳後修飾変異体。
(構成5)
配列番号2との少なくとも70%、80%、もしくは90%の相同性を有し、かつ配列番号2による代表的な軽鎖ポリペプチドの残基22、7、及び152に対応する部位からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、構成1記載の抗体、又はその翻訳後修飾変異体。
(構成6)
前記ポリペプチド鎖が、α、δ、ε、及びμからなる群から選択されるタイプの重鎖である、構成1〜5のいずれか1記載の抗体。
(構成7)
前記ポリペプチド鎖が、λ及びκから選択されるタイプの軽鎖である、構成1〜6のいずれか1記載の抗体。
(構成8)
IgA、IgA、IgA2、IgD、IgE、IgG、IgG1、IgG2、IgG3、及びIgMからなる群から選択されるクラス又はサブクラスのものである、構成1〜7のいずれか1記載の抗体。
(構成9)
前記非天然アミノ酸残基が、アミノ、カルボキシ、アセチル、ヒドラジノ、ヒドラジド、セミカルバジド、スルファニル、アジド、及びアルキニルからなる群から選択される部分を含む、構成1〜8のいずれか1記載の抗体。
(構成10)
各々の非天然アミノ酸残基が、下記式
(化1)
(式中、各々のLは、独立に、二価のリンカーであり;かつ
各々のRは、独立に、官能基である)
によるものである、構成1〜9のいずれか1記載の抗体。
(構成11)
Rが、反応基、治療的部分、又は標識部分である、構成10記載の抗体。
(構成12)
各々のRが、アミノ、カルボキシ、アセチル、ヒドラジノ、ヒドラジド、セミカルバジド、スルファニル、アジド、及びアルキニルからなる群から選択される反応基である、構成10記載の抗体。
(構成13)
各々のLが、結合、アルキレン、置換アルキレン、ヘテロアルキレン、置換ヘテロアルキレン、アリーレン、置換アリーレン、ヘテロアリーレン、及び置換ヘテロアリーレンからなる群から選択される二価のリンカーである、構成10記載の抗体。
(構成14)
1以上の治療的部分又は標識部分に連結された構成1〜13のいずれか1記載の抗体を含む、抗体コンジュゲート。
(構成15)
1以上の薬物又はポリマーに連結された前記抗体を含む、構成14記載の抗体コンジュゲート。
(構成16)
1以上の標識部分に連結された前記抗体を含む、構成14記載の抗体コンジュゲート。
(構成17)
1以上の単鎖結合ドメイン(scFv)に連結された前記抗体を含む、構成14記載の抗体コンジュゲート。
(構成18)
前記抗体が、1以上のリンカーを介して前記1以上の治療的部分又は標識部分に連結されている、構成14〜17のいずれか1記載の抗体コンジュゲート。
(構成19)
実質的に純粋である、構成1〜18のいずれか1記載の抗体を含む組成物。
(構成20)
構成1〜19のいずれか1記載の抗体を含む組成物であって、該抗体が、該組成物の全抗体質量の少なくとも95質量%である、前記組成物。
Claims (19)
- KabatもしくはChothia付番スキームによる軽鎖残基L22及びL7、重鎖残基H25、H40、H19及びH70、並びにEU付番スキームによる重鎖残基H404、H121、H180、H136及びH190からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、IgGクラスのヒト若しくはヒト化抗体、又はその翻訳後修飾変異体であって、
該翻訳後修飾が、鎖間ジスルフィド結合、鎖内ジスルフィド結合、N-結合型グリコシル化、リン酸化、O-結合型グリコシル化、メチル化、アセチル化、脂質化、GPIアンカリング、ミリストイル化、及びプレニル化からなる群から選択される1以上である、
前記ヒト若しくはヒト化抗体、又はその翻訳後修飾変異体。 - KabatもしくはChothia付番スキームによる軽鎖残基L22及びL7、重鎖残基H25及びH40、並びにEU付番スキームによる重鎖残基H404、H121、H180、H136及びH190からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、請求項1記載の抗体、又はその翻訳後修飾変異体。
- KabatもしくはChothia付番スキームによる軽鎖残基L22及びL7、並びにEU付番スキームによる重鎖残基H404、H121、H180及びH136からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、請求項1記載の抗体、又はその翻訳後修飾変異体。
- 配列番号1との少なくとも90%の同一性を有し、かつ配列番号1による代表的な重鎖ポリペプチドの残基407、124、183、139、25、40、193、19、もしくは71に対応する部位からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、請求項1記載の抗体、又はその翻訳後修飾変異体。
- 配列番号2との少なくとも90%の同一性を有し、かつ配列番号2による代表的な軽鎖ポリペプチドの残基22、及び7に対応する部位からなる群から選択される特異的部位で1以上の非天然アミノ酸残基を有するポリペプチド鎖を含む、請求項1記載の抗体、又はその翻訳後修飾変異体。
- 前記ポリペプチド鎖が、λ及びκから選択されるタイプの軽鎖である、請求項1〜5のいずれか一項記載の抗体。
- IgG1、IgG2、IgG3、及びIgG4からなる群から選択されるサブクラスのものである、請求項1〜6のいずれか一項記載の抗体。
- 前記非天然アミノ酸残基が、アミノ、カルボキシ、アセチル、ヒドラジノ、ヒドラジド、セミカルバジド、スルファニル、アジド、及びアルキニルからなる群から選択される部分を含む、請求項1〜7のいずれか一項記載の抗体。
- Rが、反応基、治療的部分、又は標識部分であり、該治療的部分又は標識部分が、標識、色素、ポリマー、水溶性ポリマー、ポリエチレングリコール若しくはその誘導体、光架橋剤、細胞毒性化合物、放射性核種、薬物、親和性標識、光親和性標識、樹脂、第二のタンパク質若しくはポリペプチド若しくはポリペプチド類似体、抗体若しくは抗体断片、金属キレーター、補因子、脂肪酸、炭水化物、ポリヌクレオチド、DNA、RNA、アンチセンスポリヌクレオチド、ペプチド、水溶性デンドリマー、シクロデキストリン、阻害性リボ核酸、バイオマテリアル、ナノ粒子、スピン標識、蛍光団、金属含有部分、放射性部分、新規官能基、他の分子と共有結合的又は非共有結合的に相互作用する基、光ケージ化部分、光異性化可能部分、ビオチン若しくはその誘導体若しくは類似体、重原子包含部分、化学切断可能基、光切断可能基、伸長側鎖、炭素結合糖、レドックス活性剤、アミノチオ酸、毒性部分、同位体標識部分、生物物理学的プローブ、リン光基、化学発光基、高電子密度基、磁性基、挿入基、発色団、エネルギー伝達剤、生体活性物質、検出可能標識、小分子、又はそれらの任意の組合せからなる群から選択される、請求項9記載の抗体。
- 各々のRが、アミノ、カルボキシ、アセチル、ヒドラジノ、ヒドラジド、セミカルバジド、スルファニル、アジド、及びアルキニルからなる群から選択される反応基である、請求項9記載の抗体。
- 各々のLが、結合、アルキレン、置換アルキレン、ヘテロアルキレン、置換ヘテロアルキレン、アリーレン、置換アリーレン、ヘテロアリーレン、及び置換ヘテロアリーレンからなる群から選択される二価のリンカーである、請求項9記載の抗体。
- 1以上の治療的部分又は標識部分に連結された請求項1〜12のいずれか一項記載の抗体を含む、抗体コンジュゲートであって、該治療的部分又は標識部分が、標識、色素、ポリマー、水溶性ポリマー、ポリエチレングリコール若しくはその誘導体、光架橋剤、細胞毒性化合物、放射性核種、薬物、親和性標識、光親和性標識、樹脂、第二のタンパク質若しくはポリペプチド若しくはポリペプチド類似体、抗体若しくは抗体断片、金属キレーター、補因子、脂肪酸、炭水化物、ポリヌクレオチド、DNA、RNA、アンチセンスポリヌクレオチド、ペプチド、水溶性デンドリマー、シクロデキストリン、阻害性リボ核酸、バイオマテリアル、ナノ粒子、スピン標識、蛍光団、金属含有部分、放射性部分、新規官能基、他の分子と共有結合的又は非共有結合的に相互作用する基、光ケージ化部分、光異性化可能部分、ビオチン若しくはその誘導体若しくは類似体、重原子包含部分、化学切断可能基、光切断可能基、伸長側鎖、炭素結合糖、レドックス活性剤、アミノチオ酸、毒性部分、同位体標識部分、生物物理学的プローブ、リン光基、化学発光基、高電子密度基、磁性基、挿入基、発色団、エネルギー伝達剤、生体活性物質、検出可能標識、小分子、又はそれらの任意の組合せからなる群から選択される、前記抗体コンジュゲート。
- 1以上の薬物又はポリマーに連結された前記抗体を含む、請求項13記載の抗体コンジュゲート。
- 1以上の標識部分に連結された前記抗体を含む、請求項13記載の抗体コンジュゲート。
- 1以上の単鎖結合ドメイン(scFv)に連結された前記抗体を含む、請求項13記載の抗体コンジュゲート。
- 前記抗体が、1以上のリンカーを介して前記1以上の治療的部分又は標識部分に連結されている、請求項13〜16のいずれか一項記載の抗体コンジュゲート。
- 請求項1〜17のいずれか一項記載の抗体を含む組成物であって、該抗体が、該組成物の全抗体質量の少なくとも80質量%である、前記組成物。
- 請求項1〜18のいずれか一項記載の抗体を含む組成物であって、該抗体が、該組成物の全抗体質量の少なくとも95質量%である、前記組成物。
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HK1203518A1 (en) | 2015-10-30 |
KR102172897B1 (ko) | 2020-11-02 |
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CA2875989A1 (en) | 2013-12-12 |
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CN104583235B (zh) | 2019-03-01 |
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PL2859017T3 (pl) | 2019-07-31 |
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AU2013270684B2 (en) | 2018-04-19 |
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EP2859017A1 (en) | 2015-04-15 |
IL236111B (en) | 2019-03-31 |
WO2013185115A1 (en) | 2013-12-12 |
ES2718478T3 (es) | 2019-07-02 |
US9738724B2 (en) | 2017-08-22 |
US20140046030A1 (en) | 2014-02-13 |
DK2859017T3 (da) | 2019-05-13 |
EP2859017B1 (en) | 2019-02-20 |
EP3505534A1 (en) | 2019-07-03 |
KR20150023630A (ko) | 2015-03-05 |
BR112014030278A2 (pt) | 2017-06-27 |
JP2015518905A (ja) | 2015-07-06 |
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